J. Org. Chem. 1989,54, 1230-1232
1230
Addition of Thiols to Styrenes: Formation of Benzylic Thioethers
Scheme I RSH
+
AIC13
H@(RSAICI$
M. Belley* and R. Zamboni Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8 Received June 16, 1988
As part of our program to find new LTDl antagonists, we were interested in synthesizing the analogues 3 of the dithioacetal 1 (SK&F no. 102,081)' and of the benzylic thioether 2 (L-655,278).2 A simple and versatile approach to this class of compounds would be the addition of a thiol to a styrene, which in turn could be obtained easily from a Wittig reaction on substituted benzaldehydes.,
1
?
-COOH
RSAIC12
k
/
\
AICI,
\
kaiyama et al. used TiC14 as the catalyst in the addition of ethanethiol to styrene and a-methylstyrene6 in cyclohexane solvent. Finally, in 1979, Screttas and MichaScrettas reported the addition of thiophenol to unfunctionalized styrenes in the presence of perchloric acid.I Using the method of Mukaiyama with functionalized styrenes and thiols, we at first obtained only polymers of styrene. However, modification of the procedure, namely, addition of TiC14dropwise to a cyclohexane solution containing the styrene and the thiol, gave some addition product (Table I). The reaction was heterogeneous and gave only poor to modest yield. In cases where the styrene moiety was not activated by a methoxyl group (entries 5, 6) and where one amide or acid function was present (entries 2-4), the rate and the yield of the reaction dropped dramatically. Unsatisfied with these reaction conditions, we discovered, much to our surprise, that AlCl, is a very good catalyst for this addition reaction. Thus, the use of 1 equiv of AlCl, for each potential complexation site, plus 1equiv in excess, afforded the Markovnikoff addition products in good yield (Table 11). Methyl esters and aromatic methyl ethers are stable under the reaction conditions, although their hydrolysis by RSH-AlCl, has been reported? Amides and acids did not inhibit the reaction (entries 5,7, 10-13), as was the case with TiC14. Aromatic thiols can also be used (entries 4 and 14). The presence of activating or deactivating substituents on the styrene influences the rate of the reaction. In the presence of a methoxy substituent, the reaction can be run at -10 "C with only 1.3 equiv of thi01.~ Conversely, a cyano-substituted styrene requires higher temperature and longer reaction time. Another peculiarity of this reaction was noticed in some cases, where radical processes interfered. This problem can be overcome by running these reactions in the dark and in the presence of 1,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Although the actual mechanism of the reaction was not studied, a plausible one is that a complex is first formed
qLo-smcooH '1 2
SR'
9
Although the Markovnikoff addition of a thiol to a double bond is a known reaction: there is an obvious lack of literature precedent when it comes to styrene substrates, probably because they polymerize so easily under acidic conditions. Only three papers report this reaction. First, in 1972, Wolf and Finke reported the use of p-TsOH as a catalyst in the addition of acidic thiols to an activated styrene, p-isopropenylphenol. Their conditions, however, failed with H2S and alkylthiols, while thiophenol gave Friedel-Crafts addition product^.^ Then, in 1973, Mu(1)Perchonock, C. D.; McCarthy, M. E.; Erhard, K. F.; Gleason, J. G.; Wasserman, M. A.; Muccitelli, R. M.; DeVan, J. F; Tucker, S. S.; Vickery, L. M.; Kirchner, T.; Weichman, B. M.; Mong, S.; Crooke, S. T.; Newton, J. F. J. Med. Chem. 1985,28,1145. (2)Young, R. N.; Gauthier, J. Y.; Frenette, R. European Patent Application 206,741,Dec 30,1986. (3)For other methods of formation of the C-S bond, see: Young, R. N.; Coombs, W.; Guindon, Y.; Rokach, J.; Ethier, D.; Hall, R. Tetrahedron Lett. 1981,22,4933.Guindon, Y.; Young, R. N.; Frenette, R. Synth. Commun. 1981,11,391. Guindon, Y.; Frenette, R.; Fortin, R.; Rokach, J. J. Org. Chem. 1983,48,1357. Gauthier, J. Y.; Bourdon, F.; Young, R. N. Tetrahedron Lett. 1986,27, 15. (4)For a review on the subject, see: Prilezhaeva, E. N.; Shostakovskii, M. F. Russ. Chem. Reo. (Engl.Transl.) 1963,32,399.For the addition reaction of thiol to olefins with AlCl,, see: Bell, R. T. U S . Patent 2,535,831, Dec 26,1950. For recent work, see: Tolstikov, G. A.; Kanzafarov, F. Ya.; Sangalov, Yu. A.; Dzemilev, U. M. Pet. Chem. USSR (Engl. Transl.) 1979,19,425. ( 5 ) Wolf, F.; Finke, H. 2. Chem. 1972,12, 180.
(6)Mukaiyama, T.; Izawa, T.; Saigo, K.; Takei, H. Chem. Lett. 1973, 335. (7)Screttas, C. G.;Micha-Screttas, M. J. Org. Chem. 1979,44, 713. (8)Node, M.; Nishide, K.; Sai, M.; Ichikawa, K.; Fuji, K.; Fujita, E. Chem. Lett. 1979,97. Node, M.; Nishide, K.; Sai, M.; Fujita, E. Tetrahedron Lett. 1978,5211. (9)Higher temperature and excess thiol resulted in the cleavage of the methoxy substituent. For examples of this reaction, see ref 8.
0022-3263/89/1954-1230$01.50/0 0 1989 American Chemical Society
J. Org. Chem., Vol. 54, No. 5, 1989 1231
Notes
Table I. Addition of Thiols to Styrenes under TiCl, Catalysis SR'
/
X
X
entry 1
styrene
thiol
3 4
COOMe
HS(CH2)2COOMe
5
COOMe
HS(CH2)&ONHBut
3.3
"'"V
2
M
e
o
m
M
e
time, h
n
8
z
yield,' %
4
54
20
10
100
576
MeorC HS(CH2)2COOMe
4
20
OC
COOMe
HS(CH2)2COOMe
5
72
35
COOMe
HSC(=O)CH3
6
20
45d
5
Bryy--,-
6
BryJ+----
"Most of the products are oils. 'H NMR spectra showed a triplet at -3.7 ppm, which is characteristic for ArCHSR. Some of the mass spectra showed a peak corresponding to [ArCH=SR]+. *Four equivalents of R'SH. No reaction. dThree equivalents of MeCOSH.
between the thiol and AlCl, (Scheme 1).lo The acidic proton then adds to the styrene to form a carbocation, which reacts with the aluminum species to yield the thioether or the chloride (see Table 11, note b). This mechanistic scheme is compatible with the fact that all these products are in equilibrium. Indeed, cu-chloroethylbenzene can be converted quantitatively to CY(ethy1thio)ethylbenzene (eq l),and benzylic sulfides can be displaced by RSH-AlCl, to give a mixture of the two sulfides. 2 EtSH 2
AlCl3
r. t. I CH2C12 100 %
SEt
SR
h
In summary, the addition of thiols to styrenes in the presence of AlCl, represents an easy and versatile approach to the synthesis of benzylic thioethers. The use of this reaction for the preparation of potent LTD, antagonists will be described in due course. Experimental Section General Procedures. Nuclear magnetic resonance spectra were recorded on a Bruker AM 250 or 3M-MHz FT spectrometer. Infrared spectra were obtained on a Perkin-Elmer Model 681 (10) These complexes, where the aluminum is sp3hybridized and the acidic proton is not attached to the sulfur atom, have been described by Hoffmann." We have recorded low-temperature'H NMR spectra of the EtSH.AlC1, complex in CD2Cl,, and our observations are in agreement with those of Hoffmann for the benzene solution.
instrument. High-resolution mass spectra were obtained a t the McGill University mass spectrometry unit on a ZAB-HS spectrometer (chemical ionization with NHJ. Purifications by flash chromatography employed 200-400-mesh silica gel supplied by E. Merck. Methyl 6-((2-(Methoxycarbonyl)ethyl)thio)-6-(3-methoxyphenyl)-3-methylhexanoate(Table I, Entry 1). To methyl 6-(3-methoxyphenyl)-3-methyl-5-hexenoate (835 mg, 3.36 mmol) and methyl 3-mercaptopropanoate (750 p L , 2 equiv) in cyclohexane (17 mL) was added TiC14 (1.9 mL, 5 equiv) dropwise. The gummy reaction mixture was stirred in the dark for 4.25 h. At 0 "C, 25% aqueous NH40Ac and EtOAc were added12 and the mixture was extracted with EtOAc. The title compound was purified by flash chromatography on silica with EtOAc-toluene, 2.597.5: IR (neat) 2920,1733,1598,1431cm-l; 'H NMR (CDCl,) 6 0.90 (2 d, 3 H), 1.00-1.45 (m, 2 H), 1.70-2.00 (m, 3 H), 2.09 (m, 1 H), 2.27 (m, 1 H), 2.45 (m, 2 H), 2.55 (m, 2 H), 3.64 (s, 3 H), 3.67 (s, 3 H), 3.69 (t, 1 H), 3.82 (s, 3 H), 6.78 (dd, 1 H), 6.85 (s, 1 H), 6.88 (d, 1 H), 7.23 (dd, 1 H); MS, m / e 369 (M + H), 368 (M+), 249 (M - SCH2CH2C0,Me);exact mass calcd for CI9HmO5S 369.1736, found 369.1734. Methyl 6- (3-Bromopheny1)-6-((2- (methoxycarbonyl)ethy1)thio)hexanoate (Table 11, Entry 6). T o methyl 6-(3bromophenyl)-5-hexenoate (28 mg, 99 pmol) and methyl 3mercaptopropanoate (22 pL, 2 equiv) in CH2Clz(1 mL) was added AlCl:, (66 mg, 5 equiv) at -10 OC, and the mixture was stirred a t room temperature for 45 min. At 0 OC, 25% aqueous NH40Ac was added.12 Extraction with EtOAc and flash chromatography of the residue on silica with EtOAc-hexane, 15:85, yielded the title thioether: IR (neat) 2920, 1737, 1590, 1565, 1430 cm-'; 'H NMR (CDC18) 6 1.30 (m, 2 H), 1.61 (m, 2 H), 1.83 (m, 2 H), 2.27 (t, 2 H), 2.48 (m, 2 H), 2.54 (m, 2 H),3.67 (s, 3 H), 3.69 (s,3 H), 3.74 (t, 1 H), 7.20 (m, 2 H), 7.37 (dt, 1 H), 7.47 (5, 1 H); MS, m / e (relative intensity) 423 (20), 422 (98), 421 (19), 420 (100,M NH4), 405 (34), 403 (30, M H),302 (23), 300 (21, M - (CH2)3C02Me - H), 285 (81), 283 (82, M - S(CH2)2C02Me);exact mass calcd for Cl7HZ4O4SBr403.0579, found 403.0583. 3 4 (l-(3-Cyanophenyl)-5-(methoxycarbonyl)-4-methyl-lpenty1)thio)propanoicAcid (Table 11, Entry 13). To a stirred
+
(11) Hoffmann, G. G. Chem. Ber. 1985, 118, 3320.
+
(12) In some cases, addition of THF facilitates the hydrolysis step. Filtration of this mixture through Celite is recommended when emulsions occur or when there are excessive quantities of insoluble aluminum salts.
1232
J. Org. Chem., Vol. 54, No. 5, 1989
Notes
Table 11. Addition of Thiols to Styrenes under AICla Catalysis SR'
room tempereturelCHzCIZ nAIC13 PR'SH X
entry
styrene
-
pR
X
thiol
n
time, h
yield," %
1
EtSH
2
2
61b
2
EtSH
2
3
57
3
Meon asn Meon HS ( CH2)&OOMe
5
0.3
59c
6
2
74-
Me02C
4
Me02C
Meon COOMe
HS(CH2)&ONMe2
6
2
77-
6
B'y
5
0.8
76
7
" 7
5
0.8
86
5
MeOzC
COOMe
COOMe
8
9 10 11 12
13
/o^""
6
COOMe
44
458
5
18
628
5
6
79de
Ncv NC
COOMe
NcD+-cooMe
NCrc 5
3.5
70dg
NCvcoo Ncyy+,--T 6
6
COOMe
COOMe
14
COOMe
HS(CH2)2COOMe
15 MeO&+cN
6.5
25
75 83
4
1.5
79d
6
1.8
84db
/
'See Table I, footnote a. ba-Chloroethylbenzene (14%) was also found. CReactionat -10 OC. d1.3equiv of R'SH. 'Addition of 0.2 equiv of BHT to the reaction mixture. fAddition of AlCl, at -10 "C. gAddition of AlCl, at 0 OC. hMixture of two isomers, 91;the major one contains the thioether at the benzylic position of the (methoxycarbony1)phenylgroup. solution of methyl 6-(3-cyanophenyl)-3-methyl-5-hexenoate (2.006 g, 8.25mmol) and 3-mercaptopropanoic acid (1.45mL, 2 equiv)
in CH2C12(80 mL) was added AlCl, (6.603g, 6 equiv), and the suspension was stirred for 25 h at room temperature in the dark. The product separated slowly as a gum. A t 0 OC, the mixture was quenched with 25% aqueous NH40Ac and EtOAc.12 The aqueous layer was acidified with AcOH and extracted with EtOAc. Flash chromatography of the residue on silica with EtOAc-hexane-AcOH, 3070:1,afforded the title thioether: IR (neat) 2500-3600 (COOH), 2950,2920,2225,1730,1710 cm-'; 'H NMR (CDC13)6 0.90(2d, 3 H), 0.97-1.45(m, 2 H), 1.70-2.00(m, 3 H),
2.07-2.33(m, 2 H), 2.54(9, 4 H), 3.66 (2s, 3 H), 3.77 (t, 1 H), 7.45 (dd, 1 H), 7.55-7.65(m, 3 H); MS, m / e (relative intensity) 368 (21), 367 (100,M + NH4), 350 (14,M + H), 244 (11, M - S(CH2),C02H);exact mass calcd for C18H2.,N04S 350.1426, found 350.1427.
Acknowledgment. We t h a n k Dr. M. A. Bernstein for running the low-temperature NMR experiments and for the s t r u c t u r e determination of the products of e n t r y 15 (Table 11).
